Seminar

Intracerebral haemorrhage
Adnan I Qureshi, A David Mendelow, Daniel F Hanley
Lancet 2009; 373: 163244
Zeenat Qureshi Stroke Research
Center, Department of
Neurology and Neurosurgery,
University of Minnesota, MN,
Minnesota, USA
(A I Qureshi MD); Department
of Neurosurgery, University of
Newcastle, Newcastle, UK
(A D Mendelow FRCS); and
Division of Brain Injury
Outcomes, Johns Hopkins
Medical Institutions,
Baltimore, MD, USA
(D F Hanley MD)
Correspondence to:
Dr Adnan I Qureshi, Department
of Neurology, University of
Minnesota, 12-100 PWB,
516 Delaware St SE, Minneapolis,
MN 55455, USA
[email protected]

Intracerebral haemorrhage is an important public health problem leading to high rates of death and disability in adults.
Although the number of hospital admissions for intracerebral haemorrhage has increased worldwide in the past
10 years, mortality has not fallen. Results of clinical trials and observational studies suggest that coordinated primary
and specialty care is associated with lower mortality than is typical community practice. Development of treatment goals
for critical care, and new sequences of care and specialty practice can improve outcome after intracerebral haemorrhage.
Specic treatment approaches include early diagnosis and haemostasis, aggressive management of blood pressure,
open surgical and minimally invasive surgical techniques to remove clot, techniques to remove intraventricular
blood, and management of intracranial pressure. These approaches improve clinical management of patients
with intracerebral haemorrhage and promise to reduce mortality and increase functional survival.

Introduction
Non-traumatic intracerebral haemorrhage results from
rupture of blood vessels in the brain. It is a major public
health problem1 with an annual incidence of 1030 per
100 000 population,1,2 accounting for 2 million (1015%)3
of about 15 million strokes worldwide each year.4
Hospital admissions for intracerebral haemorrhage
have increased by 18% in the past 10 years,5 probably
because of increases in the number of elderly people,6
many of whom lack adequate blood-pressure control,
and the increasing use of anticoagulants, thrombolytics,
and antiplatelet agents. Mexican Americans, Latin
Americans, African Americans, Native Americans,
Japanese people, and Chinese people have higher
incidences than do white Americans.2,79 These
dierences are mostly seen in the incidence of deep
intracerebral haemorrhage and are most prominent in
young and middle-aged people. Incidence might have
decreased in some populations with improved access to
medical care and blood-pressure control.810
Primary and secondary (anticoagulant-induced) intracerebral haemorrhage have similar underlying pathological changes.11 Intracerebral haemorrhage commonly
aects cerebral lobes, the basal ganglia, the thalamus,
the brainstem (predominantly the pons), and the

Search strategy and selection criteria

We based our review on personal knowledge of the subject
supplemented by data derived from multicentre randomised
trials, and selected non-randomised or observational clinical
studies. The information was identied with multiple
searches on Medline from 2002 to the present by cross
referencing the following keywords: cerebral haemorrhage,
intracerebral hemorrhage, neuroimaging, clinical
studies, randomised trials, cytotoxicity, oedema,
haemostatic treatment, factor VII, acute hypertension,
surgery, endoscopic evacuation, stereotactic surgery,
intraventricular catheter, hydrocephalus, and oral
anticoagulants. Other pertinent articles were identied
through review of bibliography from selected articles. We
also reviewed abstracts from pertinent scientic meetings.

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cerebellum as a result of ruptured vessels aected by

hypertension-related degenerative changes or cerebral
amyloid angiopathy.1 Most bleeding in hypertensionrelated intracerebral haemorrhage is at or near the
bifurcation of small penetrating arteries that originate
from basilar arteries or the anterior, middle, or posterior
cerebral arteries.12 Small artery branches of 50700 m
in diameter often have multiple sites of rupture; some
are associated with layers of platelet and brin aggregates. These lesions are characterised by breakage of
elastic lamina, atrophy and fragmentation of smooth
muscle, dissections, and granular or vesicular cellular
degeneration.12,13 Severe atherosclerosis including lipid
deposition can aect elderly patients in particular.
Fibrinoid necrosis of the subendothelium with subsequent focal dilatations (microaneurysms) leads to
rupture in a small proportion of patients.12
Cerebral amyloid angiopathy is characterised by the
deposition of amyloid- peptide and degenerative
changes (microaneurysm formation, concentric
splitting, chronic inammatory inltrates, and brinoid
necrosis) in the capillaries, arterioles, and small and
medium sized arteries of the cerebral cortex,
leptomeninges, and cerebellum.14 Cerebral amyloid
angiopathy leads to sporadic intracerebral haemorrhage
in elderly people, commonly associated with variations
in the gene encoding apolipoprotein E, and a familial
syndrome in young patients, typically associated with
mutations in the gene encoding amyloid precursor
protein.15 White-matter abnormalities (eg, leukoariosis)
seem to increase the risk of both sporadic and familial
intracerebral haemorrhage, suggesting a shared vascular
pathogenesis.16,17
Intracerebral haemorrhage associated with the taking
of oral anticoagulants typically aects patients with
vasculopathies related to either chronic hypertension or
cerebral amyloid angiopathy, which might represent
exacerbation of an existing risk of clinical and subclinical
disease.16

Pathophysiology
The regions surrounding haematomas are characterised
by oedema, apoptosis and necrosis, and inammatory
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060 min

Haematoma

Neuronal and glial

mechanical disruption,
oligaemia or ischaemia

Glutamate
release
04 h
Neuronal and
glial mechanical
stretch

Calcium inux,
mitochondrial failure

Sodium accumulation,
cytotoxic oedema,
necrosis

4 h to 7 days
Oxygen free
radicals
Thrombin,
ferrous iron,
haemin,
halotransferrin
release

AQ-4 expression in
astrocytes, breakdown
of connective tissue
in BBB, expression of
adhesion molecules

MMP
Microglial
activation
Complement
factors

TNF
Interleukin 1

Increased BBB
permeability,
vasogenic oedema

Recruitment of PMNs
and macrophages

TFNK-

Cytochrome C

Caspase activation,
apoptosis in neurons
and glia

Figure 1: Cascade of neural injury initiated by intracerebral haemorrhage

The steps in the rst 4 h are related to the direct eect of the haematoma, later steps to the products released from the haematoma. BBB=bloodbrain barrier.
MMP=matrix metallopeptidase. TNF=tumour necrosis factor. PMN=polymorphonuclear cells.

Figure 2: Progression of haemotoma and oedema on CT

Top: hyperacute expansion of haematoma in a patient with intracerebral haemorrhage on serial CT scans. Small haematoma detected in the basal ganglia and
thalamus (A). Expansion of haematoma after 151 min (B). Continued progression of haematoma after another 82 min (C). Stabilisation of haematoma after another
76 min (D). Bottom: progression of haematoma and perihaematomal oedema in a patient with intracerebral haemorrhage on serial CT scans. The rst scan (E) was
acquired before the intracerebral haemorrhage. Perihaematoma oedema is highlighted in green to facilitate recognition of progression of oedema. At 4 h after
symptom onset there is a small haematoma in the basal ganglia (F). Expansion of haematoma with extension into the lateral ventricle and new mass-eect and
midline shift at 14 h (G). Worsening hydrocephalus and early perihaematomal oedema at 28 h (H). Continued mass-eect with prominent perihaematomal oedema
at 73 h (I). Resolving haematoma with more prominent perihaematomal oedema at 7 days (J).

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T2

Pre B0

Lactate

Post B0

TTP

Figure 3: Advanced MRI of lobar intracerebral haemorrhage

Left: before craniotomy. Middle: after craniotomy for treatment of mass-eect and removal of haematoma.
Sequential T2, lactate magnetic resonance spectroscopy, and perfusion studies showed qualitative decreases of
perihaematomal oedema and perihaematomal lactate and increased occipital regional perfusion measured as time to
peak of bolus injectate (TTP) after removal of clot; TTP is represented by intensity and distribution of green colour.
Right: magnetic susceptibility images show paramagnetic inuence before surgery and limited susceptibility after
removal of the iron-containing blood clot by craniotomy. Figures provided by J Ricardo Carhuapoma (Johns Hopkins
Medical Institution, Baltimore, MD, USA).

cells.18 Haematomas induce injury (gure 1) by mechanical disruption of the neurons and glia,1 followed by
mechanical deformation causing oligaemia, neurotransmitter release, mitochondrial dysfunction, and
membrane depolarisation.1921 Dependent on the severity
of mitochondrial dysfunction, the results of injury
range from temporary metabolic suppression
(hibernation phase) to cellular swelling and necrosis. A
secondary cascade of injury is started by products of
coagulation and haemoglobin breakdown, in particular
thrombin, which activate of microglia by 4 h after
injury.2225 Activated microglia26 release products that
induce breakdown of the bloodbrain barrier, vasogenic
oedema, and apoptosis in neurons and glia.2732
Haemostasis is initiated by local activation of
haemostatic pathways and mechanical tamponade.33,34
However, about 73% of patients assessed within 3 h of
symptom onset have some degree of haematoma
enlargement35 and up to 35% have clinically prominent
enlargement35 (gure 2). Most haematoma enlargement
occurs within 3 h, although enlargement can occur up to
12 h after onset.36,37 Perihaematomal oedema increases in
volume by about 75% in the rst 24 h after intracerebral
haemorrhage,38 peaks around 56 days,39 and lasts up to
14 days.40 Early large oedema volume relative to
haematoma volume makes the greatest contribution to
outcome.41 However, oedema that is small initially can
increase in volume in the rst 24 h after haemorrhage.38
An acute hypometabolic and hypoperfusion (hibernation)
phase,42,43 with mitochondrial dysfunction44 and metabolic
failure,45 has been reported in the region surrounding
the haematoma (gure 3). Regional hypoperfusion in
clinical46,47 and experimental studies48,49 does not always
seem severe enough to induce ischaemia and might be
secondary to hypometabolism. In the presence of very
high intracranial pressure and low cerebral perfusion
pressure, the risk of global ischaemia is high. A variable
reperfusion phase lasts from 2 days to 14 days, and a
normalisation phase develops after 14 days, with
re-establishment of normal cerebral blood ow in all
viable regions.

Diagnosis, clinical features, and outcomes

Figure 4: Detection of microhaemorrhages with MRI and CT scans

Left: asymptomatic pontine microbleed (arrow) in a patient with ischaemic stroke shown as focal hypointensity
on gradient echo MRI. Right: microbleed not detected on CT scan. Figures are provided by David S Liebeskind
(University of California at Los Angeles, CA, USA).

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Although CT scanning is the rst-line diagnostic

approach, MRI with gradient echo can detect hyperacute
intracerebral haemorrhage with equal sensitivity and
overall accuracy50,51 and is more accurate for the detection
of microhaemorrhages (gure 4). Perihaematomal extravasation of intravenous contrast on CT scan can detect
ongoing bleeding.52,53 Cerebral angiography is needed to
diagnose secondary causes of intracerebral haemorrhage,
such as aneurysms, arteriovenous malformations, dural
venous thromboses, and vasculitis1,34,54,55 (gure 5). MRI
and magnetic-resonance angiography can also identify
secondary causes of intracerebral haemorrhage such as
cavernous malformations,55 although their sensitivity is
not well established.
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Events

Emergency department

Neurological, respiratory,
and haemodynamic
monitoring

24 h

Days 17

Intensive-care-unit monitoring

Days 814

Reduce intensity of monitoring if clinically indicated

Impaired consciousness
(initial Glasgow coma
scale score <8)

Early intubation and mechanical ventilation; consider monitoring of

intracranial pressure

Consider tracheostomy if
extubation not possible

Airway compromise

Early intubation and mechanical ventilation

Consider tracheostomy if
extubation not possible

High blood pressure (systolic

blood pressure 180 mm Hg)
Emergent CT scan (or MRI)

High international
normalised ratio

Intravenous antihypertensive medication titrated to eect

Oral antihypertensive
drugs may be started

Lobar haemorrhages

Consider surgical assessment in selected patients; cerebral

angiography and MRI to exclude other vascular abnormalities

Cerebellar haemorrhage

Consider surgical evacuation; cerebral angiography in

normotensive patients age 45 years

Basal ganglionic, thalamic,

or pontine haemorrhage

Conservative management; cerebral angiography in

normotensive patients age 45 years

Intraventricular
haemorrhage/hydrocephalus

Consider external ventricular drainage; cerebral angiography

in patients with isolated intraventricular haemorrhage

Rapid reversal with fresh

frozen plasma, prothrombin
concentrate, factor VII,
and vitamin K

High serum glucose (serum

glucose 111 mmol/L)

Monitor INR for recurrent elevation

Consider Intravenous insulin infusion

Oral paracetamol

Neurological deterioration

Emergency assessment, repeat CT scan, monitor intracranial pressure (if related to intracranial
hypertension), and electroencephalography (for unexplained deterioration); neurosurgical
assessment for patients with lobar or cerebellar haematomas

Oral antihypertensive drugs

Restart anticoagulation in
patients at high risk for
embolism and low risk for
recurrent intracerebral
haemorrhage

Consider surface cooling or intravascular cooling;

treat underlying aetiology

Consider short-term hyperventilation, hyperosmotic treatment, and neurosurgical assessment

Clinical or
electroencephalographic
seizures
Prophylaxis

Regular outpatient monitoring

of blood-pressure to improve
control

Oral hypoglycaemic drugs or subcutaneous insulin if required

Hyperpyrexia

Clinically signicant
intracranial mass-eect or
transtentorial herniation

Oral antihypertensive drugs

Post discharge

Consider short-term anticonvulsive treatment

H2 blockers or mucosal protectants in selected patients and intermittent pneumatic compression or low-dose heparin or
low-molecular-weight heparin (day 2 onwards) for deep-venous thrombosis in all patients

Long-term anticonvulsant
treatment in selected patients
Inferior venacaval lter or low
intensity anticoagulation in
patients with deep venous
thrombosis and high risk for
pulmonary embolism

Figure 5: Management algorithm for patients with intracerebral haemorrhage

Classic presentations, such as rapid-onset focal neurological decits, decreased consciousness, and signs of
brainstem dysfunction, are related to the size and
location of haematoma.1 Neurological deterioration is
common before56 and during57 hospital admission and is
related to early haematoma enlargement or late
worsening of oedema.58 Several descriptors of disease
severity are predictive of early death, including age,
initial score on the Glasgow coma scale (GCS),
haematoma volume, ventricular blood volume,59 and
haematoma enlargement.35
Mortality at 3 months was 34% in a review of
586 patients with intracerebral haemorrhage from
30 centres.60 In other studies it was 31% at 7 days, 59% at
1 year, 82% at 10 years, and more than 90% at 16 years.61,62
Subsequent risk of other cardiovascular events was
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4% for all stroke, 2% for intracerebral haemorrhage, and

1% for ischaemic stroke per patient-year.63 Patients with a
lobar haemorrhage had a high rate of recurrence (4% per
patient-year). Asymptomatic disease progression is
particularly common when microbleeds and white
matter abnormalities are taken into account.64 Eects of
recurrent bleeding can be changed by antihypertensive
treatment;65 whether progressive functional impairments
are equally treatable is unknown.66

Management
Overall principles
In a review of 1421 patients with intracerebral haemorrhage, care limitations or withdrawal of life-sustaining
interventions was the most common (in 68%) cause of
death.67 A state-wide survey in the USA68 showed that the
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odds of dying in hospital were associated with the

frequency of use of do-not-resuscitate orders. In another
study, in-hospital mortality was lower in patients treated
in an intensive-care neurology unit.69 These studies
provide indirect evidence that aggressive medical
management and specialist care can improve the overall
outcome in patients with intracerebral haemorrhage. In
the USA, admissions for haemorrhage to urban teaching
hospitals increased from 30% in 199091 to 49%
in 200001.5 Mortality was decreased substantially for
patients admitted to urban teaching hospitals but not
urban non-teaching hospitals and rural hospitals,
suggesting that changing trends in admissions might be
benecial.5 Trials addressing a single severity factor
(haemorrhage volume70 or haematoma enlargement71)
have been physiologically successful but without clinical
benet. These results emphasise that a single treatment
approach might accomplish its physiological goal but be
insucient to produce clinical benet, thus opening the
possibility that well organised, multimodal therapy
addressing each of the modiable factorshaematoma
volume, ventricular blood, and haematoma enlargementmight be needed.72

Early assessment and management

Airway support,1 blood-pressure control,73 intracranial
pressure treatment,74 and anticoagulation reversal75 are
commonly started in emergency departments, which
are also the site of many rst neurosurgical consultations for patients with intracerebral haemorrhage.1
Observational studies show that about 30% of patients
with supratentorial haemorrhage and almost all
patients with brainstem or cerebellar haemorrhage
have either decreased consciousness or bulbar muscle
dysfunction
necessitating
intubation.76
Rapid
deterioration, clinical evidence of transtentorial
herniation, or mass-eect or obstructive hydrocephalus
on neuroimaging should mandate an emergent
neurosurgical consultation for possible intraventricular
catheter placement or surgical evacuation and
concomitant use of hyperventilation and intravenous
mannitol7779 (gure 5). The risk of neurological
deterioration and cardiovascular instability is greatest
in the rst 24 h after symptom onset,80 and frequent
assessment of patients neurological status and
haemodynamic variables in dedicated intensive-care
units is needed.

Acute haemostatic treatment

Activated recombinant factor VII (fVIIa) promotes
haemostasis at sites of vascular injury and limits haematoma enlargement after intracerebral haemorrhage. A
randomised, double-blind, placebo-controlled phase II
trial81 treated 399 patients within 3 h of onset with
placebo or 40 m/kg, 80 m/kg, or 160 g/kg of fVIIa.
Overall, the mean increase in haematoma volume was
29% in the placebo group, compared with 1116% in
1636

the groups given fVIIa. Mortality at 90 days was 29% for

patients who received placebo and 18% for those who
received fVIIa. The phase III fVIIa for Acute
Hemorrhagic Stroke Treatment (FAST) trial71 assessed
the ecacy of fVIIa in patients with intracerebral
haemorrhage who presented within 3 h of symptom
onset. Of 821 patients, 263 received placebo, 265 received
20 g/kg, and 293 received 80 g/kg of fVIIa. The ability
of fVIIa to limit expansion was similar to the initial trial
for both the 20 g/kg and 80 g/kg doses. However, at
3 months, 24% given placebo had died or had disability
compared with 26% and 29% of patients given
20 g/kg and 80 g/kg of fVIIa, respectively; mortality
was not dierent between the groups. The rate of
arterial thrombosis was higher in patients treated with
80 g/kg of fVIIa (10%) than in those treated with
placebo (5%) or 20 g/kg of fVIIa (6%). Thus, this
pivotal trial of fVIIa did not conrm better functional
outcomes despite producing a signicant reduction in
rate of haematoma expansion. The absence of major
benet for fVIIa, despite its ability to stabilise bleeding,
suggests that additional treatments, such as surgical
evacuation after stabilisation might be needed to
change the natural history of intracerebral
haemorrhage. The FAST trial subgroup analysis82
suggested potential benet for patients younger than
70 years, with baseline haematoma volume less than
60 mL, baseline intraventricular haemorrhage volume
less than 5 mL, and time from onset less than or equal
to 25 h.

Management of mass-eects causing intracranial

hypertension
Mass-eects resulting from haematomas, oedematous
tissue surrounding haematomas, and obstructive hydrocephalus with subsequent herniation are a major cause
of death in the rst few days after intracerebral haemorrhage. Monitoring of intracranial pressure might
identify the risk of neurological deterioration83 in
patients with impaired consciousness.55 Intensive care
leading to controlled cerebral perfusion pressure of
5070 mm Hg might improve outcome.83
Two randomised trials showed no benet on regional
cerebral blood ow, neurological improvement, mortality, and functional outcomes from regular use of
intravenous mannitol boluses.8487 Therefore, only
short-term use of mannitol in patients with intracerebral haemorrhage under special circumstances,
such as transtentorial herniation or acute neurological
deterioration associated with high intracranial pressure
or mass-eect, should be considered. A single-centre
observational study suggested that aggressive, timely
reversal of transtentorial herniation through the use of
hyperventilation and osmotic drugs improved the
long-term outcome.74
The American Stroke Association (ASA) Stroke
Council88 recognises the absence of denitive clinical
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trial evidence in this specialty but recommends

monitoring of intracranial pressure in patients treated
with osmotic diuretics, cerebrospinal uid drainage via
ventricular catheter, neuromuscular blockade, and
hyperventilation. The European Stroke Initiative (EUSI)
guidelines54 recommend monitoring of intracranial
pressure for patients who need mechanical ventilation
and recommend treatment in patients who have
neurological deterioration related to increasing cerebral
oedema on neuroimaging or high intracranial pressure.
Both guidelines recommend selective use of mannitol,
hypertonic saline, and short-term hyperventilation to
maintain cerebral perfusion pressure greater than
70 mm Hg.

Management of blood pressure

The acute hypertensive response in intracerebral
haemorrhage is characterised by its high prevalence,
self-limiting nature, and prognostic signicance.89 In an
analysis of 45 330 patients with intracerebral haemorrhage, 75% had systolic blood pressure greater than
140 mm Hg and 20% greater than 180 mm Hg at
presentation.90 The high blood pressure might be
secondary to uncontrolled chronic hypertension, with
disruption of central autonomic pathways by intracerebral haemorrhage.89 High blood pressure is
associated with haematoma enlargement and poor
outcome;37 however, an exact cause and eect relation is
not proven.34 The 1999 ASA guidelines55 are based on
expert opinion and recommend lowering of blood
pressure to keep mean arterial pressure at less than
130 mm Hg in patients with a history of hypertension.
Patients with intracerebral haemorrhage treated with
intravenous infusion of calcium channel blockers
consistent with 1999 ASA guidelines within 24 h of
symptom onset tolerated treatment well and had low
rates of neurological deterioration and haematoma
expansion.36 Comparisons suggest that intravenousbolus-based regimens produce more variable bloodpressure control than do infusion-based regimens of
antihypertensive treatment.73
The current ASA Stroke Council88 guidelines recommend until ongoing clinical trials of blood pressure
intervention for intracerebral haemorrhage are completed, physicians must manage blood pressure on the
basis of the present incomplete evidence by maintaining systolic blood pressure less than 180 mm Hg in
the acute period with short half-life intravenous antihypertensive drugs. Both guidelines consider more
aggressive systolic blood-pressure lowering in the
absence of clinical signs of high intracranial pressure88
or chronic hypertension.54 Recent data suggest a greater
therapeutic benet with more aggressive lowering of
blood pressure.91 In one observational study, haematomas
enlarged in 9% of patients with systolic blood pressure
maintained below 150 mm Hg and in 30% of those with
systolic blood pressure maintained at less than
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160 mm Hg or a higher threshold.91 The Antihypertensive

Treatment of Acute Cerebral Hemorrhage (ATACH)
trial92 and the Intensive Blood Pressure Reduction in
Acute Cerebral Haemorrhage (INTERACT) trial reported
that aggressive reduction of blood pressure to less than
140 mm Hg probably decreases the rate of substantial
haematoma enlargement93 without increasing adverse
events.94 In subgroup analyses from INTERACT,93 patients
recruited within 3 h and those with an initial systolic
blood pressure of 181 mm Hg or more seemed to have the
greatest benet with aggressive lowering of blood pressure.
No dierence in rates of death and disability at 3 months
were seen between patients treated with aggressive and
conservative lowering of blood pressure in ATACH or
INTERACT studies, although the analyses were limited
by small sample sizes. Because the eect on clinical
outcome has not been fully assessed, the more
conservative targets set in the ASA Stroke Council88 and
the EUSI guidelines54 should be followed. Great caution is
advised about lowering blood pressure too aggressively
without concomitant management of cerebral perfusion
pressure.

Management of intraventricular haemorrhage and

hydrocephalus
Two clinical trials70,81 conrmed that intraventricular
haemorrhage and hydrocephalus are independent predictors of poor outcome in spontaneous intracerebral
haemorrhage.95 Impaired ow of cerebrospinal uid
and direct mass-eects of ventricular blood lead to
obstructive hydrocephalus. External drainage of
cerebrospinal uid through ventricular catheters
reduces intracranial pressure,96 but clots in the catheter
and infections prevent sustained benecial eects on
hydrocephalus and neurological status in many
patients.79,97 Shortening the length of external ventricular
drainage with early ventriculoperitoneal shunt placement98 or lumbar drainage for communicating
hydrocephalus99 might lower the rate of infections.
Substitution of lumbar drainage for external ventricular
drainage in patients with communicating hydrocephalus
might also lessen the need to change temporary
ventricular catheters and to use ventriculoperitoneal
shunts.99
Intraventricular haemorrhage is a dynamic process
that follows intracerebral haemorrhage. In a recent
study of fVIIa, 45% of 374 patients with intracerebral
haemorrhage had intraventricular haemorrhage by
24 h after presentation.100 Growth of the intraventricular
haemorrhages occurred in 17% of placebo-treated
patients and 10% of those given fVIIa. Risk factors for
growth included a baseline mean arterial pressure of
more than 120 mm Hg, large baseline volume of
intracerebral haemorrhage, presence of intraventricular
haemorrhage at baseline, shorter time from symptom
onset to rst CT scan, and lack of treatment with fVIIa.
Presence of intraventricular haemorrhage at any time
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Surgery
n/N

Control
n/N

Peto OR
95% CI

Peto OR
95% CI

Auer (1989)
Teernstra (2001)
Mendelow (2004)

11/24
12/16
56/110

15/21
7/9
71/113

036 (011116)
086 (013563)
062 (036105)

Total (95% CI)

150

143

058 (036092)

Total events: 79 (surgery), 93 (control)

Test for heterogeneity: 2=087, df=2 (p=065), l2=0%
Test for overall eect: Z=230 (p=002)
01 02 05 1 2
5 10
Favours treatment
Favours control

Figure 6: Odds ratio for death or disability in patients with lobar intracerebral haemorrhage treated
surgically or conservatively
Boxes are Petos odds ratio (OR), lines are 95% CI. Adapted with permission from Lippincott Williams
and Wilkins.108
For the STICH II trial see http://
www.ncl.ac.uk/stich/

For CLEAR-IVH see http://

clearivh.com/default.aspx

For the MISTIE trial see http://

mistietrial.com/

and growth of this haemorrhage increased the likelihood

of death or severe disability by 90 days.
To facilitate early and eective clearance of blood in
the ventricles, recent eorts have focused on
intraventricular use of thrombolytic drugs in patients
who have intraventricular haemorrhage in association
with spontaneous intracerebral haemorrhage.77,78,101 In a
randomised, double-blind, controlled trial,79 intraventricular thrombolytics given every 12 h led to faster
resolution of intraventricular haemorrhage than did
treatment with ventricular drainage alone. Two
systematic reviews of clinical studies102,103 found a
3050% reduction in mortality associated with
thrombolytic treatment for intraventricular haemorrhage. Clinical trials have not clearly shown improved
neurological outcome in survivors of intraventricular
haemorrhage. The Clot Lysis: Evaluating Accelerated
Resolution of IVH (CLEAR-IVH) trial is investigating
this issue.104
Observational studies showed encouraging results for
endoscopic removal of intraventricular haemorrhage.105107 In one study, 24 of 25 patients with intraventricular haemorrhage and obstructive hydrocephalus
had resolution of hydrocephalus after endoscopic
evacuation.107 In a single-centre, non-randomised comparison study,105 endoscopic removal of intraventricular
haemorrhage resulted in a higher rate of good recovery
at 2 months than did external ventricular drainage
alone.

Surgical evacuation
Surgical evacuation may prevent expansion, decrease
mass-eects, block the release of neuropathic products
from haematomas, and thus prevent initiation of
pathological processes. The Surgical Trial in Intracerebral
Haemorrhage (STICH) trial70 compared early surgery
(median time of 20 h from presentation to surgery) with
medical treatment. 1033 patients were randomly assigned
to early surgery or initial conservative treatment. At
6 months, early surgery had no benet compared with
initial conservative treatment: 24% versus 26% had good
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recovery or moderate disability after treatment.70 The

benets of surgery via open craniotomy can be outweighed by neural damage incurred and recurrence of
bleeding, especially in deep lesions. In a subgroup
analysis of the STICH trial, surgical treatment of lobar
haematomas and haematomas within 1 cm of the
cortical surface were most likely to benet70,108110
(gure 6). The STICH II trial has started, and will
prospectively test for benets of surgery in lobar
intracerebral haemorrhage when clots extend to within
1 cm of the cortical surface but remain intraparenchymal
without spread to the ventricular system.108 Another
potential indication for surgery is acute neurological
worsening. One report111 suggested that emergent
surgical evacuation could result in functional
independence in a quarter of patients if they had not
lost upper brainstem reexes and did not show extensor
posturing. Another prospective randomised study112
suggested that the benet of early surgery is limited to
patients presenting with initial Glasgow coma scale
scores of 8 or more or intracerebral haemorrhage
volumes of 80 mL or less.
To limit neural damage and the risk of recurrent
bleeding associated with open craniotomy, studies are
now focusing on less invasive stereotactic and
endoscopic evacuation with the use of thrombolytic
drugs.113 A randomised trial114 showed that stereotactic
evacuation of putaminal haematoma was associated
with lower mortality and better recovery to functional
independence in patients with mildly reduced
consciousness. Another trial109 randomly assigned
36 patients to stereotactic aspiration after liquefaction
with urokinase and 35 to conservative management.
Surgery showed a greater haematoma reduction (18 mL
compared with 7 mL with conservative management),
but no clinical improvement. The ongoing Minimally
Invasive Surgery plus Tissue Plasminogen Activator for
Intracerebral Hemorrhage Evacuation (MISTIE)108 trial
is designed to nd the best dose of thrombolytics capable
of removing 80% of intracerebral haemorrhage volume
by use of stereotactic aspiration followed by
catheter-based removal irrigation of intracerebral
haemorrhage with thromboytics.
The ASA Stroke Council88 and EUSI guidelines54 do
not recommend routine evacuation of supratentorial
haemorrhage by standard craniotomy within 96 h of
ictus. Both guidelines recommend surgery for patients
presenting with lobar haemorrhage within 1 cm of the
surface, particularly for those with good neurological
status who are deteriorating clinically. Guidelines
acknowledge that operative removal within 12 h, particularly with minimally-invasive methods, has the most
evidence for benecial eect and could be considered
for deep haemorrhages in the presence of mass-eect.54
However, guidelines note that very early craniotomy
might be associated with an increased risk of recurrent
bleeding.115
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Seminar

Posterior fossa surgery

Timely decompression in cerebellar haematomas can
lower morbidity and mortality related to compression of
the brainstem. In an analysis of the data from a national
stroke registry,116 patients treated surgically had signicantly greater improvement in neurological scores
than did those treated medically, independent of age
and initial severity of decits. In most institutions,
evidence of neurological deterioration is an indication
for surgical evacuation;117 although surgical intervention
before neurological deterioration might be more
benecial if there is severe fourth ventricular
compression.118 The best functional results are seen with
early craniotomy in patients with a cerebellar
haemorrhage who had an initial Glasgow coma scale
score of less than 14 or large haemorrhages (40 mL).1
Endoscopic removal of cerebellar haemorrhage119 can
also eectively remove the haematoma with lower
procedure time and a shorter period of cerebrospinal
uid drainage than with craniectomy.
The ASA Stroke Council88 and EUSI guidelines54
recommend urgent surgery for patients with cerebellar
haemorrhages with a relatively good neurological status
or haematoma larger than 3 cm who are deteriorating
clinically, or who have brainstem compression or hydrocephalus from ventricular obstruction. Cerebellar
haemorrhage is commonly complicated by obstructive
hydrocephalus120 with delayed but rapidly rising
intracranial pressure, which can be treated successfully
with external ventricular drainage.121 The consequences
of longlasting intracranial hypertension with delayed
drainage should be avoided by careful monitoring of
intracranial pressure and neurological status and use
of serial CT scans.

Neuroprotective and seizure treatment

NXY-059, a free-radical-trapping neuroprotectant,122 was
investigated in a randomised trial of 607 patients with
intracerebral haemorrhage within 6 h of symptom
onset.123 Although the use of NXY-059 was associated
with slightly less haematoma growth than use of
placebo (mean change of 45 mL vs 67 mL), on
comparison of baseline scans to those 72 h after
treatment onset, the drug had no eect on mortality at
3 months, disability, or neurological decit scores.
8% of patient with intracerebral haemorrhage have
clinical seizures124 within 1 month of symptom onset,
associated with lobar location or haematoma enlargement. However, continuous electroencephalographic
monitoring in an observational study125 showed that
28% of patients with intracerebral haemorrhage had
(predominantly subclinical) seizures within the rst
72 h of admission. Seizures were associated with
neurological worsening, an increase in midline shift,
and poorer outcomes. In another study of 45 patients
with intracerebral haemorrhage,126 subclinical seizures
and non-convulsive status epilepticus were detected
www.thelancet.com Vol 373 May 9, 2009

in 13% and 9% of the patients, respectively. Therefore, a

low threshold for obtaining electroencephalographic
studies and use of anticonvulsants in patients with
intracerebral haemorrhage might be advisable. On the
basis of risk reduction reported in observational
studies,124 a 30-day course of prophylactic anticonvulsants is recommended in patients with lobar
haemorrhage or those who develop seizures.54,88 Patients
who have a seizure more than 2 weeks after intracerebral
haemorrhage onset are at greater risk of recurrent
seizures than those who do not and might need longterm prophylactic treatment with anticonvulsants.

Management of medical complications

About 30% of patients with intracerebral haemorrhage
have gastric haemorrhages. Prophylactic H2 blockers or
drugs that can protect the mucosa lower the numbers of
such events.127 In a randomised trial,127 gastric
haemorrhages occurred in 23%, 11%, and 14% of
patients treated with placebo, ranitidine, and sucralfate,
respectively; in-hospital mortality was 28%, 11%,
and 25%.
In the rst 2 weeks, deep-venous thrombosis can be
detected by ultrasonography in 40% of patients.128
Patients with severe neurological decits and high
d-dimer concentrations are at highest risk.128 The rate of
clinical deep-venous thrombosis was 4% and pulmonary
embolism 1% within 3 months, in a combined analysis
of placebo-treated patients in fVIIa trials.129 A randomised study130 showed that intermittent pneumatic
compression decreased the occurrence of asymptomatic
deep-venous thromboembolism compared with elastic
stockings alone and should be used in all patients. The
seventh American College of Chest Physicians panel
recommends that a low-dose regimen of subcutaneous
heparin or low-molecular-weight heparin can be started
on the second day after onset of intracerebral
haemorrhage in neurologically stable patients.131 A
small study showed a low incidence of pulmonary
embolism without an incremental rate of new
intracerebral haemorrhage if low-dose heparin was
started on the second day after onset (compared with
later intervals).132 Once a deep-venous thromboembolism
develops, treatment should be given to patients at high
risk of pulmonary embolism. Inferior vena-cava lters
or a 510-day course of full-dose low-molecular-weight
heparin followed by 3 months of lower-dose lowmolecular-weight heparin are possible alternatives to
warfarin.133
10% of intensively treated patients with intracerebral
haemorrhage need tracheostomies, and early use
might reduce the risk of aspiration and long-term
mechanical ventilation.134 Recent guidelines have
placed emphasis on control of hyperthermia and
hyperglycaemia with antipyretic medication and
possibly insulin infusion in the acute period of
intracerebral haemorrhage.54,88
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Seminar

Intracerebral haemorrhage related to use of

oral anticoagulants
A population based study135 reported that intracerebral
haemorrhage associated with oral anticoagulant use
comprised 5% of all intracerebral haemorrhages in 1988,
9% in 199394, and 17% in 1999, with the observed
increase presumably due to increasing prevalence of
atrial brillation and higher rates of warfarin use.11
Although most cases associated with oral anticoagulant
use occur when international normalised ratios are
within the therapeutic range, higher ratios increase the
risk.136 Advancing age and cerebral amyloid angiopathy
are also important contributory factors to intracerebral
haemorrhage associated with oral anticoagulant use.11,137
In a multicentre study, a progressive neurological
deterioration during the rst 2448 h was seen in almost
half of patients with intracerebral haemorrhage
associated with oral anticoagulant use and a high
mortality (64%) by 6 months.138 The high mortality in
these patients was mediated by a high rate of early and
delayed haematoma enlargement139 which was
commonly associated with persistently high international normalised ratio after admission.140,141
Rapid reversal of systemic anticoagulation with a
combination of intravenous vitamin K, prothrombin
complex concentrates, or fresh frozen plasma and fVIIa
is recommended preferably within 2 h of onset.11,142,143
Prothrombin complex concentrates or fVIIa can achieve
rapid reversal although the international normalised
ratio might increase in subsequent hours owing to the
short half-lives of these drugs requiring follow-up
monitoring. In a single-centre review,141 haematomas
enlarged in 19% of patients given prothrombin complex
concentrates, 33% given fresh frozen plasma, and
50% given vitamin K. An early reversal of international
normalised ratio (within 2 h) was achieved in 84% with
prothrombin complex concentrates, 39% with fresh
frozen plasma, and 0% with vitamin K. International
normalised ratio reversal to less than 14 within 2 h was
associated with low rates of haematoma enlargement. A
retrospective study144 compared the outcomes of
neurosurgical patients with intracranial haemorrhage
treated with fresh frozen plasma and fVIIa and those
managed with fresh frozen plasma alone. International
normalised ratios returned to normal over a mean
period of 7 h in those given fVIIa and 47 h in those who
were not. More patients treated with fVIIa had good
functional outcome than did those who received only
fresh frozen plasma. Rapid reversal of international
normalised ratios also enables urgent surgical
evacuations in patients who are deteriorating
neurologically with intracerebral haemorrhage related
to oral anticoagulant use. One study145 reported a high
rate (65%) of favourable outcomes in patients with
prominent midline shift (with or without uncal
herniation) who had emergent surgical evacuation after
reversal.
1640

The clinical issue regarding reinstitution of anticoagulation is controversial. Two studies concluded that
antithrombotic drugs should be avoided where possible
in patients with acute intracerebral haemorrhage.146,147 A
subgroup at high risk of thromboembolic stroke and
low risk of recurrence might benet from long-term
anticoagulation or aspirin. Both the ASA Stroke
Council88 and the EUSI guidelines54 recommend that
warfarin can be started again in patients at a very high
risk of thromboembolism at 714 days after onset of the
original intracerebral haemorrhage.148,149

Future directions
Clinical evidence suggests the importance of three
management tasks in intracerebral haemorrhage:
stopping the bleeding,81 removing the clot,70 and controlling cerebral perfusion pressure.92 The precision
needed to achieve these goals and the degree of benet
attributable to each clinical goal would be precisely
dened when the results of trials in progress become
available. An NIH workshop150 identied the importance
of animal models of intracerebral haemorrhage and of
human pathology studies. Use of real-time, high-eld
MRI with three-dimensional imaging and highresolution tissue probes is another priority. Trials of
acute blood-pressure treatment and coagulopathy
reversal are also medical priorities. And trials of
minimally invasive surgical techniques including
mechanical and pharmacological adjuncts are surgical
priorities. The STICH II trial should determine the
benet of craniotomy for lobar haemorrhage. A better
understanding of methodological challenges, including
establishment of research networks and multispecialty
approaches, is also needed.150 New information created
in each of these areas should add substantially to our
knowledge about the ecacy of treatment for
intracerebral haemorrhage.
Contributors
All authors contributed equally to the preparation of this Seminar.
Conicts of interest
AIQ has received funding from National Institutes of Health
RO-1-NS44976-01A2 (medication provided by ESP Pharma), American
Heart Association Established Investigator Award 0840053N, and
Minnesota Medical Foundation (Minneapolis, MN, USA). ADM is the
director of the Newcastle Neurosurgery Foundation, and has received
honoraria for attending Advisory Committee Meetings for Codman and
for Novo Nordisk. DFH receives funding through the US Food and
Drug Administration orphan-drugs programme grant 5RO1-FD 001693,
National Institute of Neurological Disorders and Stroke (NINDS)
planning grant, 1R34-NS056638, MISITIE: NINDS, 1R01-NS 046309,
Jerey and Harriet Legum professorship, Genentech, sponsored
research agreement; he also has disavowed interest in this patent
(Johns Hopkins University use patent application # 10/509,694) and
has received an honorarium from Novo Nordisk.
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